Process for the manufacture of enol ethers of alpha, beta-unsaturated steroid ketones



Patented Nov. 21, 1944' UNITED. PATENT OFFICE rnoocssroa THE MANUFACTURE OF ENOL ETHERS or a,fl -UNSATURATED STEROID KETONES I Heinrich Ktiste'r, Berlin-Charlottenburg, Gen many, assignor to Schering Corporation, Bloomfield, N. J., a corporation of New Jersey No Drawing. Application June 8, 1940, Serial No.

- 339,486. In Germany June 16, 19,39 v

20 Claims. (Cl. 260-3974) Lazeotropisme Bruxelles 1918 and furtherpubli- This invention relates to eno1 derivatives of v c-unsaturated steroid ketones and'most particularly to enol ethers of said. compounds and a method of making the same. j

In U. S. application Serial No. 308,206 a process is described involving the manufacture of cyclic acetals of keto steroids; said process consisting in reacting the lnetosteroids.with polyvalent alcohols or alkylene oxides preferably in the presence of a.

catalyst; In U. S'.' application SeriaLNo. 233,346,

which hasissuedas Patent No. 2,294,433, dated September 1, 1942, a process is described for the conversion of diketones of the steroid seriesto the correspondinghydroxy ketones by forming first mono enol ethers of said diketones and thenreducin'g the free keto group to the hydroxy group.

-I have found that; on reacting nip-unsaturated ketosteroids with alcohols, eno1 ethers may be obtained in a simple manner and with a very good yield. This good yield of enol ethers is obtained cations of this author.

When using dior poly ketones of the steroid series as starting material it is possible to obtain mono as well as di or poly enol ethers. The fori: mation of the different enol ethers depends upon the amount of alcohol employed for the reaction. It is, however, possible to obtain mono enol ethers in a very good yield when reacting the ketone with a small excess of the equivalent amount of the alcohol.

The mono enol ethers of steroid diketones, such as androstendione, are of especial importance; for, by reduction by mean-s of methods known .to the expert for transforming a keto group into a hydroxy group, 'hydroxy-ketone eno1 ethers, such as testosterone enol ether, are obtained which by continuously removing the water formed dur- 1 3 ing reaction. In a manner herein described more in detail even enol ethers of a complicated structure may be synthesized by reacting alcohols of complicated structure or of high molecular weight with ketosteroids under the conditions set'forth, e. g. cholesteryl enol ethers of cholestenone, or enolethers of alcohols, whose 'so-called ortho esters-such asorthoformic acid esters, areun known.

I According to the iprocesso f this application enol ethers are obtained .in a very good yield by di-, rectly reacting steroid 'ketones with alcohols, preferably in the presence 'of catalysts, at thev same time removing thewaterformed e. g. by distillation asan azeotropic mixtureor by :combini gfthe water by means .of anhydrous salts like calcium chloride, sodiumsulfate and the'like. Without continuously removing the water, "the manufacture'of enol ethers of, complicated structure is very difiicult andthe yield is rather poor.

For performing the reaction a specialapparatus issuitably employed, as described, for instance, in the textbook Organic Syntheses vol.

either have a pronounced physiological activity or can readily be converted into the corresponding hydroxy ketones, such as testosterone, by hydrolizing the'enol ether, for instance, by treatment with dilute mineral acids.

The enol ethers such as testosterone benzylenol ether and the j like are characterized by a very protracted. physiological action. Tested by the capons combte'st the testosterone benzyl enol ether was six times more active than testosterone.

The action of testosterone lasted for five days whilst the action of the equivalent amount of said eno1 ether lasted for twenty days. The testosterons cyclohexyl'enol ether was about twice as active as testosterone. j

The invention may be illustrated by the following examples without, however, being limited to them.

Example 1 2.85 gs. of androstendio'ne are dissolved in com. of benzene, thereto are added 1.2 gs. of benzyl alcohol and a few crystals of p-toluene sulfonic acid and the'reaction mixture is heated to boiling in an apparatus adapted for distillation of an azeotropic mixture. The azeotropic mixture of benzene and water distills'from the reaction mix-' tureand is freed from water after condensation, the distillate separating into two-layers, one of which contains the benzene and theother the water whereafter' the benzene free of water is allowed to flow back intothe reaction vessel. After boiling for 16 hours the mixture is evaporated to dryness in vacuo. On triturating the residue with alcohol, crystals are formed. The

crystals are isolated and recrystallized from alcohol containing suitably a small amount of pyridine. The androstendione-3,l7-enol benzylic ether-3 melts at 164 C. and shows a specific rota- .tion of (a).D =-65.3 in dioxane.

Its configuration is shown by the following formula:

CH3 CH3 Example 2 2.84 gs. of androstendione are dissolved in 70 cos. of benzene. 1.1 gs. of cyclohexyl-alcohol and a few crystals of p-toluene sulfonicacid are added. The mixture is then heated to boiling in the above described special apparatus. The azeotropic mixture of benzene and water distills from the mixture, is freed from water and the Water-free benzene reconducted to the reaction vessel. is evaporated to dryness in vacuo. On triturating with alcohol the residue crystallizes. The crystals are isolated and recrystallized from alcohol under addition of a small amount of pyridine. The androstendione-enol cyclohexyl ether melts at 164 C. and shows a specific rotation of (a)n ='l9' in dioxane.

Its structure is shown by the following formula:

OHa (Ha After boiling for 16 hours the mixture.

Example 3 1.92 gs. of cholestenone and 1.93 gs. of cholesterol are dissolved in 80 cos. of benzene and after addition of p-toluene-sulfonic acid reacted according to Example 1. The cholestenone cholesteryl enol ether formed is recrystallized from acetone. It melts at 218 C. and shows a specific rotation of (a)D =90 in benzene.

The structure of said compound is shown by By reacting pregnendione and benzyl alcohol in benzene in the presence of p-toluene sulfonic acid according to Example 1 the pregnendione benzyl enol etheris obtained and purified by recrystallization from methanol. It melts at 192 C. and has a specific rotation of (a)D =50.3 in dioxane.

Its structure is as follows:

CHz/\(IIH:4 2: A/L/ Q L/J Example 5 3.84 gs. of cholestenone and 1 g. of n.butyl alcohol are dissolved in 80 cos. of benzene, mixed with 10 mgs. of hydrogene chloride in absolute crystallizes on treating with alcohol.

alcohol and boiled in a special apparatus while continuously removing by distillation the water formed. After 16 hours of boiling, an alcoholic solution of potassium hydroxide is added, the mixture poured into water and extracted with ether. The ethereal solution is washed with water, dried and evaporated. The remaining oil After purifying by means of n.propyl alcohol the cholestenone n.butyl enol ether melts at 97 C. and shows a specific rotation of (a)D =-93 in dioxane. It has the formula CH: on: f CHLCHLCHLCHZ-Ow \/1 7 Example 6 In a charge according to Example 5 instead of hydrochloric acid p-toluene sulfonic acid is applied and to the mixture there are added 2 gs. of anhydrous sodium sulfate. In this case no distillationis necessary, but the mixture is boiled for 16 hours under reflux. It is then worked up according to Example yielding the same substance in a yield of 48.5%.

Of course, various changes may be made in the details disclosed in the foregoing specification without departing from the invention and the claims annexed hereto.

What I claim is:

1. Process for the manufacture of enol ethers of c p-unsaturated steroid ketones comprising reacting an ya-unsaturated ketosteroid with an alcohol and removing the water formed during reaction.

2. A process according to claim 1, comprising using an aromatic alcohol as reaction component.

3. A process according to claim 1 comprising using benzyl alcohol as reaction component.

4. A process for the manufacture of enol ethers of cap-unsaturated steroid ketones comprising reacting an i c-unsaturated ketosteroid with an alcohol in the, presence of anacidic catalyst.

5. A process for the manufacture of enol ethers of a,,8-unsaturated steroid ketones comprising reacting an cap-unsaturated ketosteroid with an alcohol in a solvent forming with water an azeotropic mixture and distilling oil the water of reaction.

6. A process for the manufacture of enol ethers of n p-unsaturated steroid ketones comprising reacting an cap-unsaturated ketosteroid with an alcohol in the presence of an acidic catalyst in a solvent capable of forming an azeotropic mixture with water on distillation, and removing the water formed during reaction, continuously from said azeotropic mixture.

7. A process according to claim 1 comprising using androstendione as' starting material.

8. A process according to claim 1 comprising using pregnendione as starting material.

9. A process according to claim 4 comprising using p-toluene sulfonic acid as a catalyst.

10. A process according to claim 4 comprising using hydrochloric acid as a catalyst;

11. A process according to claim 5 comprising using benzene as a solvent.

12. Androstendione-3,1'7-benzy1 enol ether-3 of M. P. 164 C. and (a)D =65.3 in dioxane.

13. Testosterone benzyl enol ether of M. P. 153 C. and (a)D =110.3 in dioxane.

. 14. Pregnendione benzyl enol ether of" M. P. 192 C. and (a)D =-50.3 in diozane.

15. A process according to claim 1 comprising removing the water formed during reaction by means of anhydrous salts.

16. A process for the manufacture of enol ethers of hydroxy ketones of the steroid series comprising reacting an cap-unsaturated steroid poly ketone with an alcohol, removing the water formed during reaction, and reducing free keto groups present in known manner to transform said free keto groups into hydroxy groups.

17. A process according to claim 16, wherein the enol ether of the hydroxy ketone of the steroid series is hydrolized to the corresponding hydroxy ketone.

18. A process for the manufacture of testosterone, comprising reacting androstendione with an alcohol to form the 3-eno1 ether, removing the water formed during reaction, reducing the mono-3-en0l ether of androstendione-3,17 ob-' tained to the corresponding 3-enol ether of androstenol-l'l-one-Zi, and hydrolizing the latter to testosterone.

19. The benzyl enol ether of an u, 3-unsaturated steroid ketone. I

20. The benzyl enol ether of a 3-ket0-A4,5-

steroid having at the 17-position a member of alcohol and keto groups.

the class consisting of HEINRICH KCis'rER. 

